Stereoselective renal secretion of carbenicillin in rabbits: Role of the organic anion transporter at the renal brush border membrane

Itoh, Tomoo; Nakaura, Hiromi; Koyano, Shin-ichi; Tsuda, Yasuyuki; Yamada, Hideo

doi:10.1002/(sici)1520-636x(1998)10:4<349::aid-chir10>3.0.co;2-#

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…Differences in renal secretion by the organic anion transporter are at most 2-fold between stereoisomers. [7][8][9] Differences in transport (or affinity) of the organic cation transporter are at most 4-fold between enantiomers. [3][4][5][6] The exception is the transport of verapamil enantiomers by the organic cation transporter, which shows the difference in affinity between the enantiomers by 17.5-fold.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Renal tubular secretion is also stereoselective when chiral drugs are actively secreted by transporters. [3][4][5][6][7][8][9] Moreover, intestinal absorption of some chiral drugs seems to be stereoselective, since various drug transporters are involved in intestinal absorption. [10][11][12][13][14][15] Methotrexate (MTX or L-amethopterin) is an analog of folic acid (FA) and is used clinically as an antineoplastic and antirheumatic agent.…”

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Stereoselectivity of the folate transporter in rabbit small intestine: Studies with amethopterin enantiomers

et al. 2001

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Stereoselectivity of the folate transporter was examined using rabbit intestinal brush border membrane vesicles (BBMV). Methotrexate (MTX) and the antipode (D-amethopterin) were used as model substrates of the transporter. Folic acid (FA) and MTX were actively taken up into BBMV in the presence of an H+ gradient. Initial uptake of FA and MTX was concentration-dependent with Km values of 1.5 and 1.6 microM for FA and MTX, respectively. FA and MTX mutually inhibited uptake in a competitive manner, with Ki values being similar to the corresponding Km values, demonstrating that FA and MTX share the folate transporter. D-Amethopterin also inhibited FA uptake competitively, with a Ki value approximately 60-fold greater than that of MTX, showing that the affinity of the D-isomer (D-amethopterin) to the folate transporter is much less than that of the L-isomer (MTX). The extent of stereoselectivity observed in the present study is consistent with the previously reported differences in plasma concentration between amethopterin enantiomers following oral administration in humans.

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Section: Discussionmentioning

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Stereoselectivity of the folate transporter in rabbit small intestine: Studies with amethopterin enantiomers

et al. 2001

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“…5,6 Intestinal absorption and renal tubular secretion are also stereoselective when drug transporters are involved in these processes. 5,7 Moreover, isomerization is known to occur in the body. 8 In spite of many reports on stereoselective binding and isomerisomer interactions of chiral drugs, [1][2][3][4]9,10 information on stereoselectivity and isomer-isomer interactions in the binding of diastereomeric ␤-lactam antibiotics is limited.…”

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Stereoselective binding and degradation of sulbenicillin in the presence of human serum albumin

et al. 2001

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Binding of sulbenicillin (SBPC) isomers to human serum albumin (HSA) was stereoselective. There were at least two classes of binding sites on HSA for SBPC isomers. At the stereoselective high affinity site, binding was in favor of R-SBPC, the binding constant of R-SBPC being approximately 2.3-fold greater than that of S-SBPC. By using site marker ligands, it was revealed that the stereoselective site was Site I (warfarin binding site). Affinity for the low affinity (nonstereoselective) site was similar for the diastereomers, approximately 7--30-fold lower than for the stereoselective site. R-SBPC and S-SBPC appeared to displace each other competitively at both binding sites. On the other hand, R-SBPC was degraded much faster than S-SBPC in the presence of HSA, with a degradation rate constant approximately 7-fold greater for R-SBPC than for S-SBPC. The degradation of R-SBPC was inhibited in the presence of warfarin and dependent on the concentration of R-SBPC bound to Site I. The results demonstrate that Site I is responsible for the stereoselective degradation.

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Effects of Chirality on Toxicity

Nilos¹,

Gan²,

Schlenk³

2009

General, Applied and Systems Toxicology

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Chirality is a prominent feature of the living world, and also occurs in man‐made chemicals, especially pharmaceuticals and agrochemicals. The significance of chirality has long been recognized in relation to the biological activity of natural compounds and synthetic drugs. At a molecular level, chirality is ubiquitous in the building blocks of proteins, carbohydrates, nucleic acids, lipids and steroids. Thus, stereoselectivity can be expected in the interactions of chiral chemicals with biological molecules. It is not uncommon in racemic mixtures of chiral drugs or agrochemicals to have only one of its two (or more) enantiomers responsible for most or all of the desired activity. The other enantiomer(s) are all too often assumed to be inactive of little or no important activity. The last 30 years has seen a significant increase in published work highlighting the important relationship between molecular geometry and bioactivity, particularly for chiral pharmaceuticals and agrochemicals. However, a sizable number of chiral drugs and agrochemicals are still available as racemates with relatively little or no information with regard to the toxicological properties of the individual enantiomers. The persistent reluctance to acknowledge the risks associated with the chirality of a chemical is no longer justified. Chiral technology has developed to a point where we are allowed several options in enantiomer resolution and preparation techniques, which in turn offer new avenues for human and environmental toxicologists to explore the stereochemical properties of these ubiquitous agents. This chapter discusses some of the toxicological complexities that could result from chirality, in the hope of highlighting the importance of enantioselective considerations in both mammalian and ecotoxicology.

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Stereoselective renal secretion of carbenicillin in rabbits: Role of the organic anion transporter at the renal brush border membrane

Cited by 8 publications

References 26 publications

Stereoselectivity of the folate transporter in rabbit small intestine: Studies with amethopterin enantiomers

Stereoselectivity of the folate transporter in rabbit small intestine: Studies with amethopterin enantiomers

Stereoselective binding and degradation of sulbenicillin in the presence of human serum albumin

Effects of Chirality on Toxicity

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